RESUMEN
In this study, we have designed, synthesized and tested three series of novel dihydropteridone derivatives possessing isoindolin-1-one or isoindoline moieties as potent inhibitors of PLK1/BRD4. Remarkably, most of the compounds showed preferable inhibitory activity against PLK1 and BRD4. Compound SC10 exhibited excellent inhibitory activity with IC50 values of 0.3â¯nM and 60.8â¯nM against PLK1 and BRD4, respectively. Meanwhile, it demonstrated significant anti-proliferative activities against three tumor-derived cell lines (MDA-MB-231 IC50â¯=â¯17.3â¯nM, MDA-MB-361 IC50â¯=â¯8.4â¯nM, and MV4-11 IC50â¯=â¯5.4â¯nM). Moreover, SC10 exhibited moderate rat liver microsomal stability (CLintâ¯=â¯21.3⯵L·min-1·mg-1), acceptable pharmacokinetic profile (AUC0-tâ¯=â¯657â¯ng·h·mL-1, oral bioavailability of 21.4â¯%) in Sprague-Dawley rats, reduced hERG toxicity, acceptable PPB and CYP450 inhibition. Further research indicated that SC10 could induce MV4-11 cell arrest at the S phase and apoptosis in a dose-dependent manner. This investigation provided us with an initial point for developing novel anticancer agents as dual inhibitors of PLK1 and BRD4.
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Antineoplásicos , Neoplasias , Inhibidores de Proteínas Quinasas , Animales , Ratas , Antineoplásicos/farmacología , Antineoplásicos/metabolismo , Proteínas de Ciclo Celular , Línea Celular Tumoral , Proliferación Celular , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Neoplasias/tratamiento farmacológico , Proteínas Nucleares/metabolismo , Ratas Sprague-Dawley , Relación Estructura-Actividad , Factores de Transcripción , Proteínas que Contienen Bromodominio/antagonistas & inhibidores , Indoles/química , Indoles/farmacología , Quinasa Tipo Polo 1/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacologíaRESUMEN
HPK1 also referred to as MAP4K1, belongs to the category of mammalian STE20-like protein serine/threonine kinases. Its physiological function involves the down-regulation of T cell signals, and it is regarded as a new immune checkpoint of tumor immunology. In this study, we commenced our investigation with the hit compounds, focusing the efforts on structural optimization and SAR exploration to identify a novel class of 2,4-diaminopyrimidine HPK1 inhibitors. Notably, compound 14g exhibited a remarkable inhibitory effect on HPK1 kinase (IC50 = 0.15 nM), significantly suppressed the phosphorylation of the downstream adaptor protein SLP76 (pSLP76 IC50 = 27.92 nM), and effectively stimulated the secretion of the T cell activation marker IL-2 (EC50 = 46.64 nM). In vitro microsomal stability assay, compound 14g showed moderate stability in HLMs with T1/2 = 38.2 min and CLint = 36.4 µL·min-1·mg-1 proteins. In vivo pharmacokinetic studies, compound 14g demonstrated heightened plasma exposure (AUC0-inf = 644 ng·h·mL-1), extended half-life (T1/2 = 9.98 h), and reduced plasma clearance (CL = 52.3 mL·min-1·kg-1) compared to the reference compound after a single intravenous dose of 2 mg/kg in rats. These results indicated that compound 14g emerged as a promising inhibitor of HPK1.
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Diseño de Fármacos , Inhibidores de Proteínas Quinasas , Proteínas Serina-Treonina Quinasas , Pirimidinas , Pirimidinas/farmacología , Pirimidinas/química , Pirimidinas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Humanos , Relación Estructura-Actividad , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Animales , Estructura Molecular , Ratas , Relación Dosis-Respuesta a Droga , Masculino , Simulación del Acoplamiento Molecular , Ratas Sprague-DawleyRESUMEN
Dual inhibitors of JAK2 and FLT3 can synergistically control the development of acute myeloid leukemia (AML), and overcome secondary drug resistance of AML that is associated with FLT3 inhibition. We therefore designed and synthesized a series of 4-piperazinyl-2-aminopyrimidines as dual inhibitors of JAK2 and FLT3, and improved their selectivity for JAK2. Screening cascades revealed that compound 11r exhibited inhibitory activity with IC50 values of 2.01, 0.51, and 104.40 nM against JAK2, FLT3, and JAK3, respectively. Compound 11r achieved a high selectivity for JAK2 at a ratio of 51.94, and also showed potent antiproliferative activity in HEL (IC50 = 1.10 µM) and MV4-11 (IC50 = 9.43 nM) cell lines. In an in vitro metabolism assay, 11r exhibited moderate stability in human liver microsomes (HLMs), with a half-life time of 44.4 min, and in rat liver microsomes (RLMs), with a half-life of 143 min. In pharmacokinetic studies, compound 11r showed moderate absorption (Tmax = 5.33 h), with a peak concentration of 38.7 ng/mL and an AUC of 522 ng h/mL in rats, and an oral bioavailability of 25.2%. In addition, 11r induced MV4-11 cell apoptosis in a dose-dependent manner. These results indicate that 11r is a promising selective JAK2/FLT3 dual inhibitor.
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Antineoplásicos , Leucemia Mieloide Aguda , Ratas , Humanos , Animales , Relación Estructura-Actividad , Línea Celular Tumoral , Inhibidores de Proteínas Quinasas/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/metabolismo , Microsomas Hepáticos/metabolismo , Apoptosis , Tirosina Quinasa 3 Similar a fms/metabolismo , Proliferación Celular , Antineoplásicos/uso terapéutico , Janus Quinasa 2/metabolismoRESUMEN
Hepatocellular carcinoma (HCC) is the terminal phase of multiple chronic liver diseases, and evidence supports chronic uncontrollable inflammation being one of the potential mechanisms leading to HCC formation. The dysregulation of bile acid homeostasis in the enterohepatic circulation has become a hot research issue concerning revealing the pathogenesis of the inflammatory-cancerous transformation process. We reproduced the development of HCC through an N-nitrosodiethylamine (DEN)-induced rat model in 20 weeks. We achieved the monitoring of the bile acid profile in the plasma, liver, and intestine during the evolution of "hepatitis-cirrhosis-HCC" by using an ultra-performance liquid chromatography-tandem mass spectrometer for absolute quantification of bile acids. We observed differences in the level of primary and secondary bile acids both in plasma, liver, and intestine when compared to controls, particularly a sustained reduction of intestine taurine-conjugated bile acid level. Moreover, we identified chenodeoxycholic acid, lithocholic acid, ursodeoxycholic acid, and glycolithocholic acid in plasma as biomarkers for early diagnosis of HCC. We also identified bile acid-CoA:amino acid N-acyltransferase (BAAT) by gene set enrichment analysis, which dominates the final step in the synthesis of conjugated bile acids associated with the inflammatory-cancer transformation process. In conclusion, our study provided comprehensive bile acid metabolic fingerprinting in the liver-gut axis during the inflammation-cancer transformation process, laying the foundation for providing a new perspective for the diagnosis, prevention, and treatment of HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Ratas , Animales , Carcinoma Hepatocelular/metabolismo , Ácidos y Sales Biliares/metabolismo , Neoplasias Hepáticas/metabolismo , Hígado/metabolismo , Inflamación/metabolismoRESUMEN
The pharmacological inhibition of soluble epoxide hydrolase (sEH) was shown to reduce inflammation and pain. Herein, we described a series of newly synthesized sEH inhibitors with the trident-shaped skeleton. Intensive structural modifications led to the identification of compound B15 as a potent sEH inhibitor with an IC50 value of 0.03 ± 0.01 nM. Furthermore, compound B15 showed satisfactory metabolic stability in human liver microsomes with a half-time of 197 min. In carrageenan-induced inflammatory pain rat model, compound B15 exhibited a better therapeutic effect compared to t-AUCB and Celecoxib, which demonstrated the proof of potential as anti-inflammatory agents for pain relief.
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Inhibidores Enzimáticos , Epóxido Hidrolasas , Animales , Benzamidas/farmacología , Benzamidas/uso terapéutico , Inhibidores Enzimáticos/química , Dolor , Ratas , Relación Estructura-Actividad , Urea/farmacología , Urea/uso terapéuticoRESUMEN
The elevation of epoxy-fatty acids through inhibition of soluble epoxide hydrolase (sEH) is efficient for the treatment of inflammatory and pain-related diseases. Herein, we reported the discovery of a series of benzamide derivatives containing urea moiety as sEH inhibitors. Intensive structural modifications led to the identification of compound A34 as a potent sEH inhibitor with good physicochemical properties. Molecular docking revealed an additional hydrogen-bonding interaction between the unique amide scaffold and Phe497, contributing to sEH inhibition potency enhancement. Compound A34 exhibited outstanding inhibitory activity against human sEH, with an IC50 value of 0.04 ± 0.01 nM and a Ki value of 0.2 ± 0.1 nM. It also showed moderate systemic drug exposure and oral bioavailability in vivo metabolism studies. In carrageenan-induced inflammatory pain rat model, compound A34 exhibited a better therapeutic effect compared to t-AUCB and Celecoxib. Metabolism studies in vivo together with an inflammatory pain evaluation suggest that A34 may be a viable lead compound for the development of highly potent sEH inhibitors.
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Inhibidores Enzimáticos , Epóxido Hidrolasas , Animales , Benzamidas/farmacología , Benzamidas/uso terapéutico , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Humanos , Simulación del Acoplamiento Molecular , Dolor , Ratas , Solubilidad , Urea/farmacologíaRESUMEN
OBJECTIVE: To analyze the factors affecting the early prognosis of patients undergoing repeat tricuspid valve surgery due to severe tricuspid regurgitation after left-sided valvular surgery. METHOD: We retrospectively analyzed 76 patients undergoing repeat tricuspid valve surgery due to severe tricuspid regurgitation after left-sided valvular surgery at Peking University International Hospital between October 2017 and February 2021. Patients were divided into two groups, according to preoperative weight control and whether the adjusted diuretic dose exceeded 40 mg of furosemide (or the equivalent dose). The factors affecting the early prognosis were analyzed through postoperative follow up. RESULTS: Thirty-five male patients (46.1%), aged 57±13 years, were enrolled in the study. For the patients who received a preoperative same dose of furosemide ≥40 mg/day and a same dose of furosemide <40 mg/day, the baseline data basically were the same. There were 76 patients (100%) who were followed up. Endpoint events during the follow up were as follows: Six patients (7.9%) died, two patients (2.6%) were admitted to the hospital or transferred to the intensive care unit due to cardiac insufficiency, and other conditions such as severe tricuspid regurgitation on repeat ultrasound, bilateral lower extremity edema, and inability to reduce or stop diuretics were found in five cases (6.6%). Compared with the group with the same dose of furosemide <40 mg/day group, the ≥40 mg/day group had a higher incidence of endpoints (12, 27.3% vs. 1, 3.1%, P = 0.006). CONCLUSION: In patients undergoing repeat tricuspid valve surgery due to severe tricuspid regurgitation after left-sided valvular surgery, a diuretic response was associated with surgical prognosis. Compared with the low-dose furosemide group, the high-dose group (≥40 mg/) had a significantly increased incidence of early events.
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Implantación de Prótesis de Válvulas Cardíacas , Insuficiencia de la Válvula Tricúspide , Diuréticos/uso terapéutico , Furosemida , Implantación de Prótesis de Válvulas Cardíacas/efectos adversos , Humanos , Masculino , Pronóstico , Estudios Retrospectivos , Resultado del Tratamiento , Válvula Tricúspide/diagnóstico por imagen , Válvula Tricúspide/cirugía , Insuficiencia de la Válvula Tricúspide/diagnóstico , Insuficiencia de la Válvula Tricúspide/etiología , Insuficiencia de la Válvula Tricúspide/cirugíaRESUMEN
OBJECTIVES: The purpose of our study was to evaluate the potential of cervical lymph node shear wave elastography (SWE) to quantify the lymph node stiffness (kilopascals) noninvasively among patients with lymph node-first presentation of Kawasaki disease (NFKD), patients with bacterial cervical lymphadenitis (BCL), and healthy children (HC). We further aimed to investigate the correlation of laboratory data and lymph node stiffness to provide a reference basis for the early diagnosis of NFKD. METHODS: Lymph node stiffness measurements were prospectively performed in 47 patients with NFKD, 56 patients with BCL, and 56 HC using SWE. Cervical SWE was compared in the groups. Factors associated with increased cervical lymph node stiffness were studied. RESULTS: The mean elasticity of the largest cervical lymph nodes was significantly higher in the BCL group than the NFKD and HC groups (mean elasticity ± SD, 16.37 ± 2.45, 12.22 ± 2.64, and 7.81 ± 1.67 kPa, respectively; P < .01), with a cutoff of 14.55 kPa (area under the curve, 0.885; sensitivity, 89%; and specificity, 76%). In patients with NFKD, interleukin 6 (standardized ß = 0.363; P = .01), alanine aminotransferase (standardized ß = 0.253; P = .03), aspartate aminotransaminase (standardized ß = 0.536; P = .047), and total bilirubin (standardized ß = 0.486; P < .01) values were correlated with increased largest cervical lymph node stiffness. CONCLUSIONS: Cervical lymph node stiffness was different between NFKD and BCL. Shear wave elastography is a potential method to identify clinically distinguishable early NFKD.
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Diagnóstico por Imagen de Elasticidad , Linfadenitis , Síndrome Mucocutáneo Linfonodular , Niño , Elasticidad , Humanos , Ganglios Linfáticos/diagnóstico por imagen , Síndrome Mucocutáneo Linfonodular/diagnóstico por imagenRESUMEN
Garden-cultivated Ginseng (GG) and mountain-cultivated Ginseng (MG) both belong to Panax Ginseng C. A. Meyer. However, the effective substances which can be used to distinguish GG from MG remain obscure. Therefore, the purpose of this study was to screen for discriminating markers that can assist in the correct identification of GG and MG. HPLC Q-TOF/MS and various chemometrics methods were used to analyze the chemical profiles of 13 batches of Ginseng and to explore the characteristic constituents of both GG and MG. The hepatocyte-protecting effects of GG and MG were investigated through a paclitaxel-induced liver injury model. Through a combination of correlation analysis and bioinformatic techniques, markers for differentiation between GG and MG were ascertained. A total of 40 and 41 compounds were identified in GG and MG, respectively, and 15 characteristic ingredients contributed significantly to the discrimination of GG from MG. Correlation analysis and network pharmacology were applied and ginsenosides Rg1, Re, Rb1, Rc, Rb2, and Rg3 were found to be discriminating markers of GG and MG. Six markers for the identification of GG and MG were screened out by a step-wise mutually oriented "chemical profiling-pharmaceutical effect" correlation strategy, which is of great significance for future quality assessment of Ginseng products.
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Quimioinformática/métodos , Panax/química , Sustancias Protectoras/química , Sustancias Protectoras/farmacología , Animales , Biomarcadores Farmacológicos , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Cromatografía Líquida de Alta Presión , Jardines , Ginsenósidos/análisis , Ginsenósidos/química , Espectrometría de Masas , Paclitaxel/efectos adversos , Panax/crecimiento & desarrollo , Sustancias Protectoras/farmacocinética , Ratas Sprague-DawleyRESUMEN
Green and enhanced extraction of bioactive ingredients from medicinal plants has become a hot research field, and deep eutectic solvents have been considered as a novel kind of sustainable solvents in the extraction process. In this study, hydrogen bond acceptor (choline chloride, etc.) and hydrogen bond donor (l-malic acid, etc.) were used to prepare different kinds of deep eutectic solvents to extract coumarins from Cortex Fraxini. The extraction conditions, including the composition and moisture content of deep eutectic solvents, extraction time, and liquid-solid ratio, were systematically optimized basing on the extraction yield of coumarins. To further investigate the extraction mechanism, Fourier transform infrared spectroscopy was performed, and the microstructures of Cortex Fraxini powders were observed before and after extraction using scanning electron microscope. Results showed that the novel ultrasound-assisted extraction with conditions of deep eutectic solvent containing betaine/glycerin (1:3), aqueous solution (20%), solid-liquid ratio (15 mg/mL), and extraction time (30 min) exhibited the best extraction yields for the four target coumarins and much better extraction efficiency than with conventional solvent extractions. This suggests that the new ultrasound-assisted deep eutectic solvent extraction could be used as a green and high-efficient approach for extraction of the main coumarins from Cortex Fraxini.
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Cumarinas/aislamiento & purificación , Medicamentos Herbarios Chinos/química , Tecnología Química Verde , Extractos Vegetales/aislamiento & purificación , Ondas Ultrasónicas , Aesculus , Betaína/química , Cumarinas/química , Glicerol/química , Extractos Vegetales/química , Solventes/química , Agua/químicaRESUMEN
OBJECTIVE: We aimed to evaluate the performance of the newly developed deep learning Radiomics of elastography (DLRE) for assessing liver fibrosis stages. DLRE adopts the radiomic strategy for quantitative analysis of the heterogeneity in two-dimensional shear wave elastography (2D-SWE) images. DESIGN: A prospective multicentre study was conducted to assess its accuracy in patients with chronic hepatitis B, in comparison with 2D-SWE, aspartate transaminase-to-platelet ratio index and fibrosis index based on four factors, by using liver biopsy as the reference standard. Its accuracy and robustness were also investigated by applying different number of acquisitions and different training cohorts, respectively. Data of 654 potentially eligible patients were prospectively enrolled from 12 hospitals, and finally 398 patients with 1990 images were included. Analysis of receiver operating characteristic (ROC) curves was performed to calculate the optimal area under the ROC curve (AUC) for cirrhosis (F4), advanced fibrosis (≥F3) and significance fibrosis (≥F2). RESULTS: AUCs of DLRE were 0.97 for F4 (95% CI 0.94 to 0.99), 0.98 for ≥F3 (95% CI 0.96 to 1.00) and 0.85 (95% CI 0.81 to 0.89) for ≥F2, which were significantly better than other methods except 2D-SWE in ≥F2. Its diagnostic accuracy improved as more images (especially ≥3 images) were acquired from each individual. No significant variation of the performance was found if different training cohorts were applied. CONCLUSION: DLRE shows the best overall performance in predicting liver fibrosis stages compared with 2D-SWE and biomarkers. It is valuable and practical for the non-invasive accurate diagnosis of liver fibrosis stages in HBV-infected patients. TRIAL REGISTRATION NUMBER: NCT02313649; Post-results.
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Aprendizaje Profundo , Diagnóstico por Imagen de Elasticidad/métodos , Hepatitis B Crónica/complicaciones , Cirrosis Hepática/diagnóstico por imagen , Adulto , Biopsia , China , Diagnóstico Diferencial , Femenino , Humanos , Cirrosis Hepática/patología , Masculino , Estudios ProspectivosRESUMEN
Purpose To investigate the diagnostic performance of two-dimensional (2D) shear-wave elastography (SWE) in chronic hepatitis B. Materials and Methods This prospective multicenter study from January 2015 to January 2016 was conducted at 12 hospitals and included 654 participants with chronic hepatitis B who had undergone liver biopsy and 2D SWE examination. Participants were divided into chronic infection and chronic hepatitis groups. The diagnostic performance of 2D SWE was compared with the aspartate amino transferase-to-platelet ratio index (APRI), the Fibrosis-4 index (FIB-4), and transient elastography (TE) by using a DeLong test and was also compared between two subgroups. Dual cutoff values for cirrhosis were determined with multilevel likelihood ratio analysis. Results Overall, 402 participants with chronic hepatitis B were enrolled (154 with chronic infection and 248 with chronic hepatitis). The areas under the receiver operating characteristic curve of 2D SWE (0.87; 95% confidence interval [CI]: 0.83, 0.90) were higher than those of TE (0.80; 95% CI: 0.68, 0.88), APRI (0.70; 95% CI: 0.65, 0.74), and FIB-4 (0.73; 95% CI: 0.69, 0.78) in cirrhosis. The high area under the receiver operating characteristic curve (0.92; 95% CI: 0.87, 0.96) was achieved in the chronic infection group and was significantly higher than that of the chronic hepatitis group (0.84; 95% CI: 0.78, 0.88; P = .017). Dual cutoff values with the likelihood ratios below 0.1 and above 10 (8.4 kPa and 11.0 kPa to rule out and rule in a diagnosis of cirrhosis, respectively) were effectively determined in chronic infection; a total of 81.2% (125 of 154) participants with cirrhosis were definitively diagnosed. Conclusion The performance of two-dimensional (2D) shear-wave elastography (SWE) was higher than that of other noninvasive methods. 2D SWE was most effective in ruling in and ruling out cirrhosis in participants with chronic infection, which may prompt antiviral treatment. © RSNA, 2018 Online supplemental material is available for this article.
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Diagnóstico por Imagen de Elasticidad/métodos , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/diagnóstico , Cirrosis Hepática/diagnóstico por imagen , Cirrosis Hepática/etiología , Adulto , Femenino , Humanos , Hígado/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Reproducibilidad de los ResultadosRESUMEN
PURPOSE: Pericardiectomy is the definitive treatment option for constrictive pericarditis and is associated with a high prevalence of morbidity and mortality. However, information on the associated outcomes and risk factors is limited. We aimed to report the mid-term outcomes of pericardiectomy from a single center in China. METHODS: We retrospectively reviewed data collected from patients who underwent pericardiectomy at our institute from April 2018 to January 2023. RESULTS: Eighty-six consecutive patients (average age, 46.1 ± 14.7 years; 68.6 men) underwent pericardiectomy through midline sternotomy. The most common etiology was idiopathic (n = 60, 69.8%), and 82 patients (95.3%) were in the New York Heart Association function class III/IV. In all, 32 (37.2%) patients underwent redo sternotomies, 36 (41.9%) underwent a concomitant procedure, and 39 (45.3%) required cardiopulmonary bypass. The 30-day mortality rate was 5.8%, and the 1-year and 5-year survival rates were 88.3% and 83.5%, respectively. Multivariable analysis revealed that preoperative mitral insufficiency (MI) ≥moderate (hazard ratio [HR], 6.435; 95% confidence interval [CI] [1.655-25.009]; p = 0.007) and partial pericardiectomy (HR, 11.410; 95% CI [3.052-42.663]; p = 0.000) were associated with increased 5-year mortality. CONCLUSION: Pericardiectomy remains a safe operation for constrictive pericarditis with optimal mid-term outcomes.
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Pericardiectomía , Pericarditis Constrictiva , Humanos , Pericarditis Constrictiva/cirugía , Pericarditis Constrictiva/mortalidad , Pericarditis Constrictiva/fisiopatología , Pericarditis Constrictiva/diagnóstico por imagen , Estudios Retrospectivos , Masculino , Pericardiectomía/efectos adversos , Pericardiectomía/mortalidad , Persona de Mediana Edad , Femenino , Factores de Riesgo , Adulto , Resultado del Tratamiento , Factores de Tiempo , China/epidemiología , Medición de Riesgo , Anciano , Complicaciones Posoperatorias/mortalidad , Complicaciones Posoperatorias/etiología , Esternotomía/efectos adversos , Esternotomía/mortalidadRESUMEN
The emergence of multidrug-resistant bacteria along with a declining pipeline of clinically useful antibiotics has led to the urgent need for the development of more effective antibacterial agents to treat drug-resistant bacteria. We previously discovered compound OB-158 with potent antibacterial activity but exhibited poor oral bioavailability. Herein, a systematic structural optimization of OB-158 to improve pharmacokinetic profiles yielded 26 novel biaryloxazolidinone analogues, and their activities against Gram-positive S. aureus, multidrug resistant S. aureus and Enterococcus faecalis were evaluated. Remarkably, compound 8b was identified with potent antibacterial activity against S. aureus (MIC = 0.06 µg/mL), MSSA (MIC = 0.125 µg/mL), MRSA (MIC = 0.06 µg/mL), LRSA (MIC = 0.125 µg/mL) and LREFa (MIC = 0.5 µg/mL). Compound 8b was demonstrated as a promising candidate through druglikeness evaluation including metabolism in microsomes and plasma, Caco-2 cell permeability, plasma protein binding, cytotoxicity, and inhibition of CYP450 and human monoamine oxidase. Notably, compound 8b displayed excellent PK profile with appropriate T1/2 of 1.49 h, high peak plasma concentration (Cmax = 2320 ng/mL), high plasma exposure (AUC0-t = 8310 h ng/mL), and superior oral bioavailability (F = 68.1 %) in Sprague-Dawley rats. Ultimately, in vivo efficacy of compound 8b in a mouse model of LRSA systemic infection was also demonstrated. Taken together, compound 8b represents a promising drug candidate for the treatment of linezolid-resistant Gram-positive bacterial strains infection.
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Antibacterianos , Linezolid , Pruebas de Sensibilidad Microbiana , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Humanos , Animales , Linezolid/farmacología , Relación Estructura-Actividad , Células CACO-2 , Ratones , Estructura Molecular , Relación Dosis-Respuesta a Droga , Staphylococcus aureus/efectos de los fármacos , Ratas , Farmacorresistencia Bacteriana/efectos de los fármacos , Masculino , Enterococcus faecalis/efectos de los fármacos , Oxazolidinonas/farmacología , Oxazolidinonas/química , Oxazolidinonas/síntesis química , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Left atrial (LA) function is a very important prognostic indicator for many cardiovascular diseases. In this study, we aimed to determine whether LA function is impaired in children with Kawasaki disease (KD) and to analyze the relationships between LA deformation and conventional echocardiographic parameters and laboratory markers. METHODS: A total of 50 KD patients during different disease phases and 50 age- and sex-matched controls were retrospectively analyzed. Patients in the acute phase based on coronary artery dilation (CAD) were subdivided into Group I (with CAD) and Group II (without CAD) and compared. RESULTS: During the acute phase, KD patients had a lower peak LA longitudinal strain (PLALS), a lower LA strain peak during LA contraction (LASct), and a lower LA strain rate peak during LA contraction (LASRct) than the controls. The PLALS, LASct and LASRct began to increase during the subacute phase, and during the convalescent phase, all LA strains in patients had recovered to normal compared with the control subjects. Subgroup analysis revealed that, compared with Group II, Group I had higher C-reactive protein (CRP) and serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels; however, there were no significant differences in LA strains. Only the PLALS during the acute phase was negatively correlated with left ventricular mass index, CRP and NT-proBNP. CONCLUSIONS: In patients with KD, LA function is impaired during the acute phase, and this impairment is transient. Two-dimensional speckled tracking echocardiography is a useful tool for detecting subclinical LA dysfunction.
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Fibrilación Atrial , Aneurisma Coronario , Síndrome Mucocutáneo Linfonodular , Humanos , Niño , Estudios Retrospectivos , Síndrome Mucocutáneo Linfonodular/complicaciones , Síndrome Mucocutáneo Linfonodular/diagnóstico por imagen , Ecocardiografía/métodos , Atrios Cardíacos/diagnóstico por imagenRESUMEN
The unavailability of adequate lipid reference standards is a major challenge for accurate quantitative analysis of lipidomics. Based on the discovery of regularity and predictability for lipids in chromatography-mass spectrometry behaviors, "target compound-structure correlation-analytical parameter database" protocol and "modeling-prediction" strategy were carried out to calculate the relative coefficients of analytical parameters within each subclass. Then the relevant LC-tandem-MS parameters of unknown lipids were predicted and a quantification parameter database for 4081 lipids was established and validated. Reference standards-independent accurate determination for lipidomics was achieved with the parameter's database and applied to monitor the change of lipid metabolism in the plasma of whole course of health-hepatitis-cirrhosis-hepatocellular carcinoma (HCC). Combined Student's t test, orthogonal partial least squares discrimination analysis (OPLS-DA) and binary logistic regression-ROC analysis, lipid biomarkers for differentiating health from each disease and differentiating different stages of disease were identified and the pathogenesis of HCC was preliminarily clarified. The established methodology would shed light on comprehensive and accurate quantitative lipidomics and exploring the pathomechanism and potential therapeutic targets of HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Lipidómica , Carcinoma Hepatocelular/diagnóstico , Neoplasias Hepáticas/diagnóstico , Lípidos/química , Espectrometría de MasasRESUMEN
ATR kinase is essential to the viability of replicating cells responding to the accumulation of single-strand breaks in DNA, which is an attractive anticancer drug target based on synthetic lethality. Herein we design, synthesize, and evaluate a novel series of fused pyrimidine derivatives as ATR inhibitors. As a result, compound 48f, with an IC50 value of 0.0030 µM against ATR, displayed strong monotherapy efficacy in ataxia-telangiectasia mutated (ATM) kinase-deficient tumor cells LoVo, SW620, OVCAR-3 cell lines with IC50 values of 0.040 µM, 0.095 µM, 0.098 µM, respectively. More importantly, the combination of 48f with AZD-1390, cisplatin, oxaliplatin, and olaparib respectively resulted in synergistic activity against HT-29, HCT116, A549, MCF-7, MDA-MB-231 cells. Moreover, 48f showed a favorable pharmacokinetic profile with a bioavailability of 30.0% in SD rats, acceptable PPB, high permeability (Papp A to B = 8.23 cm s-1 × 10-6), and low risk of drug-drug interactions. Collectively, compound 48f could be a promising compound for further investigation.
Asunto(s)
Antineoplásicos , Neoplasias Ováricas , Humanos , Ratas , Animales , Femenino , Apoptosis , Línea Celular Tumoral , Pirimidinas/farmacología , Ratas Sprague-Dawley , Antineoplásicos/farmacología , Diseño de Fármacos , Inhibidores de Proteínas Quinasas/farmacología , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteínas de la Ataxia Telangiectasia Mutada/metabolismoRESUMEN
Polo like kinase 1 (PLK1) is a serine/threonine kinase that is widely distributed in eukaryotic cells and plays an important role in multiple phases of the cell cycle. Its importance in tumorigenesis has been increasingly recognized in recent years. Herein, we describe the optimization of a series of novel dihydropteridone derivatives (13a-13v and 21g-21l) possessing oxadiazoles moiety as potent inhibitors of PLK1. Compound 21g exhibited improved PLK1 inhibitory capability with an IC50 value of 0.45 nM and significant anti-proliferative activities against four tumor-derived cell lines (MCF-7 IC50 = 8.64 nM, HCT-116 IC50 = 26.0 nM, MDA-MB-231 IC50 = 14.8 nM and MV4-11 IC50 = 47.4 nM) with better pharmacokinetic characteristics than BI2536 in mice (AUC0-t = 11 227 ng h mL-1vs 556 ng h mL-1). Moreover, 21g exhibited moderate liver microsomal stability and excellent pharmacokinetic profile (AUC0-t = 11227 ng h mL-1, oral bioavailability of 77.4%) in Balb/c mice, acceptable PPB, improved PLK1 inhibitory selectivity, and no apparent toxicity was observed in the acute toxicity assay (20 mg/kg). Further investigation showed that 21 g could arrest HCT-116 cells in G2 phase and induce apoptosis in a dose-dependent manner. These results indicate that 21g is a promising PLK1 inhibitor.
Asunto(s)
Antineoplásicos , Ratones , Animales , Proliferación Celular , Antineoplásicos/farmacología , Inhibidores de Proteínas Quinasas , Proteínas de Ciclo Celular , Proteínas Serina-Treonina Quinasas , Línea Celular Tumoral , ApoptosisRESUMEN
Recent studies have shown that dysregulation of carboxyl submetabolome homeostasis is closely related to the occurrence and development of hepatocellular carcinoma (HCC). However, it is still a challenge to quantify carboxyl metabolites with high efficiency by conventional methods due to their species diversity and nature differences. Moreover, there are few studies on carboxyl submetabolome profiling during the whole progression of HCC. In this study, a convenient and efficient workflow for absolute quantification of carboxyl submetabolome was established based on the 4-(diethylamino)-butylamine (DEABA)-labeled polarity-response-homodispersed strategy. After optimizing derivation conditions with response surface methodology (RSM), the reaction only needed 1 min at room temperature, which radically simplified the labeling process. Compared with nonderivatization, the gaps of polarities and responses of the analytes were narrowed by DEABA labeling, realizing the polarity-response-homodispersion. Then resolution and sensitivity in HPLC-MS/MS were improved significantly. Ultimately, the workflow was applied to monitor carboxyl metabolic profile in human plasma of the whole progressive course of hepatocellular carcinoma. Combined with analysis of variance (ANOVA), orthogonal partial least squares discrimination analysis (OPLS-DA), Bayesian linear discriminant analysis (BLDA) and other data mining methods, the biomarkers of "health-hepatitis-cirrhosis-HCC" were screened out, and the diagnostic model was established. Furthermore, the relevancy between carboxyl submetabolome disorders and the pathogenesis of HCC was investigated. The developed method has the characteristics of high sensitivity, high coverage and high practicability, which is suitable for the study of biomarkers of carboxyl submetabolome in the whole progression of HCC.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/diagnóstico , Espectrometría de Masas en Tándem , Butilaminas , Metabolómica/métodos , Neoplasias Hepáticas/diagnóstico , Teorema de BayesRESUMEN
PM2.5 exposure can induce or exacerbate heart failure and is associated with an increased risk of heart failure hospitalization and mortality; however, the underlying mechanisms remain unclear. This study focuses on the potential mechanisms underlying PM2.5 induction of cardiomyocyte programmed necrosis as well as its promotion of cardiac function impairment in a mouse model of heart failure with preserved ejection fraction (HFpEF). HFpEF mice were exposed to concentrated ambient PM2.5 (CAP) (CAP group) or filtered air (FA) (FA group) for 6 weeks. Changes in myocardial pathology and cardiac function were documented for comparisons between the two groups. In vitro experiments were performed to measure oxidative stress and mitochondrial permeability transition pore (mPTP) dynamics in H9C2 cells following 24 h exposure to PM2.5. Additionally, co-immunoprecipitation was conducted to detect p53 and cyclophilin D (CypD) interactions. The results showed exposure to CAP promoted cardiac function impairment in HFpEF mice. Myocardial pathology analysis and in vitro experiments demonstrated that PM2.5 led to mitochondrial damage in cardiomyocytes and, eventually, their necrosis. Moreover, our experiments also suggested that PM2.5 increases mitochondrial reactive oxygen species (ROS), induces DNA oxidative damage, and decreases the inner mitochondrial membrane potential (ΔΨm). This indicates the presence of mPTP opening. Co-immunoprecipitation results showed a p53/CypD interaction in the myocardial tissue of HFpEF mice in the CAP group. Inhibition of CypD by cyclosporin A was found to reverse PM2.5-induced mPTP opening and H9C2 cell death. In conclusion, PM2.5 induces mPTP opening to stimulate mitochondria-mediated programmed necrosis of cardiomyocytes, and it might exacerbate cardiac function impairment in HFpEF mice.